deficit on NIH Stroke Scale examination
Head CT does not show hemorrhage or nonstroke cause of deficit. Patient’s age is >18 years
Exclusion criteria
Minor or rapidly improving symptoms
Seizure at onset of stroke
Major surgery within 14 days
Prior stroke or serious head trauma with past 3 months
Known history of intracranial hemorrhage
Sustained blood pressure >185/110 mmHg
Aggressive treatment necessary to lower blood pressure
Symptoms suggestive of subarachnoid hemorrhage
Gastrointestinal or genitourinary hemorrhage in last 21 days
Arterial puncture at a noncompressible site within 7 days
Heparin administration within 48 h with elevated aPTT
Prothrombin time >15 s
Platelet count <100,000 μL
Serum glucose <50 mg/dL or >400 mg/dL
Relative contraindications
Large stroke with NIH Stroke Scale score >22
CT shows evidence of large MCA territory infarction (sulcal effacement or blurring of gray‐white junction in greater than one third of MCA territory)
Relative contraindications for the 3‐ to 4.5‐h treatment window
History of prior stroke and diabetes mellitus
NIH Stroke Scale >25
Oral anticoagulant use regardless of INR
Age >80 years
INR, international normalized ratio; MCA, middle cerebral artery; NIH, National Institutes of Health; aPTT, activated partial thromboplastin time.
Source: Miller J, Hartwell C, Lewandowski C. 2012, Stroke treatment using intravenous and intra‐arterial tissue plasminogen activator. Curr Treat Options Cardiovasc Med. 2012; 14:273–83. © 2012, Springer Nature.
Some literature suggests that placing the patient supine may increase cerebral perfusion, but it also increases intracranial pressure, and this remains an area of uncertainty and investigation. Obviously, supine positioning is not advised in a patient who has clinical evidence of elevated intracranial pressure. As always, the risk of aspiration must be considered as well [13].
Ultimately, the goals for prehospital care of the stroke patients include rapid evaluation, stabilization, neurologic examination, and expedited transport to an appropriate destination hospital [15]. Early communication to the destination hospital is important. Studies have shown that such notification gives time for the stroke team to arrive in the ED and decreases the time from ED arrival to computed tomography (CT) imaging and increased rates of IV tissue plasminogen activator (tPA) administration [16, 17].
Definitive treatment options
Sussman and Fitch reported the first use of IV thrombolytics to treat acute ischemic stroke in the late 1950s [18]. However, early studies using either streptokinase or urokinase resulted in high incidences of ICH. Therefore, these therapeutic agents were abandoned for the treatment of stroke until the 1970s, when advanced imaging technology could rule out the possibility of ICH prior to thrombolytic administration and allow for a more definitive diagnosis of ischemic stroke. Unfortunately, high rates of ICH secondary to streptokinase treatment persisted in later trials, and ultimately led to the early termination of the Multicenter Acute Stroke Trial‐Italy (MAST‐I) and Multicenter Acute Stroke Trial‐Europe (MAST‐E) in the mid‐1990s, as well as the abandonment of streptokinase as a viable ischemic stroke treatment option [19]. Around the same time as the MAST‐E trial, several trials of tPA, which was thought to have a better risk–benefit profile compared to other thrombolytics, were conducted and failed to demonstrate favorable outcomes.
However, it was felt that the use of tPA held promise if a correct dose and the right population of patients were selected [19]. In 1995, the NINDS trial demonstrated improved functional outcomes at 3 months as measured by the National Institutes of Health Stroke Scale score, the modified Rankin score (mRS), and other neurologic assessment tools in highly selected ischemic stroke patients treated within 3 hours of symptom onset [20]. Patients treated with tPA were 30% more likely to have minimal to no disability at 3 months compared with patients treated with placebo (absolute benefit of 12%; number needed to treat [NNT] = 8), which was found to persist at 12 months [20, 21]. Based upon these findings, in 1996, the U.S. Food and Drug Administration approved the use of intravenous tPA for the treatment of acute ischemic stroke within 3 hours of the onset of symptoms [19]. One criticism of the NINDS trial was that patients treated with tPA had less severe stroke scores than the placebo group, which altered the measured outcome. However, after further analysis, it was determined that the difference in the stroke severity did not account for the differences [22].
Additionally, evidence has emerged supporting the extension of the 3‐hour treatment window to 4.5 hours [23]. The European Cooperative Acute Stroke Study (ECASS III) randomized patients to tPA or placebo within 4.5 hours of symptom onset and found that patients receiving tPA were significantly more likely to have favorable outcomes (52.4% vs. 45.2%; NNT = 14) [23].
Equally as important, among patients who present within the treatment time windows for tPA, those treated sooner have much better odds of having good outcomes. Specifically, patients treated up to 90 minutes from symptom onset have an odds ratio (OR) of having improved functional outcomes of 2.6 (NNT = 4.5), compared to an OR of 1.6 (NNT = 9) for those treated between 91 and 180 minutes, and an OR of 1.3 (NNT = 14.1) for those treated between 181 and 270 minutes [23]. It is the general consensus and the recommendation of the AHA/ASA that tPA be given in the setting of acute ischemic stroke when it can be performed by personnel trained in the care of acute stroke and without protocol violations [9].
Intra‐arterial tPA and endovascular thrombectomy are two other options for stroke patients who fall outside of the 4.5 hour window or who have not substantially improved after IV tPA therapy [23]. The decision to use intra‐arterial tPA is made after angiographic imaging and requires an interventional neuroradiologist with specific expertise. The PROACT II (Prolyse in Acute Cerebral Thromboembolism) study evaluated the safety and efficacy of this procedure using prourokinase injected into middle cerebral artery occlusions. The study results indicated that there was a significant improvement in outcome (measured as independent function at 90 days) in 40% of patients in the treated group, compared with 25% of patients in the placebo group [24].
For patients with ischemic stroke due to large vessel occlusion (LVO), endovascular thrombectomy has emerged as a promising therapeutic intervention. In the Endovascular Therapy Following Imaging Evaluation for Ischemic Stroke (DEFUSE‐3) trial, investigators assessed functional outcomes for patients treated for a proximal middle cerebral artery or internal carotid artery occlusion with endovascular therapy plus standard medical therapy (endovascular‐therapy group) versus standard medical therapy alone (medical‐therapy group). Patients were treated within 6 to 16 hours since they were last known well. The trial was stopped early for efficacy after 182 patients were randomized. In the endovascular‐therapy group, there was a significantly higher proportion of patients (45% vs. 17% in the medical‐therapy group, p < 0.001) who were functionally independent at 90 days, defined as a mRS score of 0 to 2. Furthermore, the 90‐day mortality rate was lower at 14% in the endovascular‐therapy group versus 26% in the medical‐therapy group (p = 0.05). Notably, there was no significant difference between groups in the frequency of symptomatic intracranial hemorrhage (7% vs. 4%, p = 0.75) or serious adverse events (43% vs. 53%, p = 0.18) [25].
A second group of investigators (DAWN Trial Investigators) evaluated the efficacy of